Australian Researchers Illustrate Use of ctDNA in Metastatic Breast Cancer

Researchers recently described a prospective circulating tumor DNA (ctDNA) testing program for patients with metastatic breast cancer (mBC) to determine its feasibility to guide patient management, which historically relies on solid tumor biopsies.

Writing in PloS Medicine, the authors noted that ctDNA, a minimally invasive blood test, can add to traditional tumor biopsies for molecular profiling, enabling faster, real-time decisions about treatment. Moreover, they added, “the spatial and temporal heterogeneity of a patient’s tumor cannot be captured through a single biopsy, as it can evolve during the course of treatment.”

In this program, the results changed the management of 40 patients, including 20 who were referred to clinical trials.

The researchers conducted the study at the Peter MacCallum Cancer Centre in Melbourne, Australia, enrolling 234 patients (median age 54) between June 2015 and October 2018, to analyze samples for somatic mutations.

Median follow-up was 15 months (range 1-46). By type of mBC, 78% were ER+/HER2-;12% were HER2+; and 10% were triple negative disease. Most patients were newly diagnosed or had disease progression after 2 or more therapies.

In addition, longitudinal plasma testing was performed in a subset of patients (n = 67, 28.6%), according to physician choice, for repeated molecular profiling or disease monitoring; in some cases, actionable mutations were discovered later at the time of relapse.

Researchers used a multiplexed droplet digital PCR (ddPCR) assay to find somatic mutations to identify hotspot mutations in PIK3CA, ESR1, ERBB2, and AKT1. They said they chose these targets and assay because of the availability of targeted therapies as well as a fast turnaround time for results.

At the same time, in order to compare results and discover actionable mutations, subsets of samples were analyzed via next-generation sequencing (targeted panel sequencing and low-coverage whole-genome sequencing [LC-WGS]. The panel was developed in-house and included 394 amplicons across 39 genes.

Before starting treatment, the results were discussed at a multidisciplinary breast cancer meeting where joint decisions were made; the authors noted that clinical interpretation of ctDNA-based results in mBC have not yet been established, so all results were made available to providers.

ddPCR and targeted panel sequencing identified at least 1 actionable mutation at baseline in 80/234 (34.2%) and 62/159 (39.0%) of patients tested, respectively. Combined, both methods detected an actionable alteration in 104/234 patients (44.4%) through baseline or serial ctDNA testing.

LC-WGS was performed on 27 patients from the cohort, uncovering several recurrently amplified regions including 11q13.3 encompassing CCND1.

Higher ctDNA levels were linked with inferior overall survival, regardless of assessment method (ddPCR, targeted sequencing, or LC-WGS).

There were several limitations to the study, the authors noted. A little more than a third of the patients were lost to follow-up. They also said that the impact of ctDNA testing on survival outcomes was not included, and that future research should quantify the clinical and health economic impact of ctDNA testing in mBC.

Reference

Bujak AZ, Weng C-F, Silva, et al. Circulating tumour DNA in metastatic breast cancer to guide clinical trial enrolment and precision oncology: A cohort study. Published online October 1, 2020. PLoS Med. doi: 10.1371/journal.pmed.1003363​